Citations

AbstractBackgroundAdenosine signaling has been implicated in several neurological and psychiatric disorders. Previously, we found that astrocytic excitatory amino acid transporter 2 (EAAT2) and aquaporin 4 (AQP4) are downregulated in the striatum of mice lacking type 1 equilibrative nucleoside transporter (ENT1).MethodsTo further investigate the gene expression profile in the striatum, we preformed Illumina Mouse Whole Genome BeadChip microarray analysis of the caudate–putamen (CPu) and nucleus accumbens (NAc) inENT1 null mice. Gene expression was validated byRT‐PCR, Western blot, and immunofluorescence. Using transgenic mice expressing enhanced green fluorescence protein (EGFP) under the control of the glial fibrillary acidic protein (GFAP) promoter, we examinedEGFPexpression in anENT1 null background.ResultsGlial fibrillary acidic protein was identified as a top candidate gene that was reduced in ENT1 null mice compared to wild‐type littermates. Furthermore, EGFP expression was significantly reduced in GFAP‐EGFP transgenic mice in an ENT1 null background in both the CPu and NAc. Finally, pharmacological inhibition or siRNA knockdown of ENT1 in cultured astrocytes also reduced GFAPmRNAlevels.ConclusionsOverall, our findings demonstrate thatENT1 regulatesGFAPexpression and possibly astrocyte function.

Abstract Advances in surgical procedures and improvements in patient outcomes have resulted from applications of new technologies in the operating room over the past three decades. All surgeons would be excited about the possibilities of improving their resections of tumors for patients with cancer if a new technology were introduced to facilitate this. In this issue of ACS Nano, Karabeber et al. use a hand-held Raman scanner to probe the completeness of resection of glioblastoma multiforme (GBM), the most malignant brain cancer, in a genetically engineered mouse model. They show that the hand-held scanner could accurately detect gold–silica surface-enhanced Raman scattering nanoparticles embedded within the GBM, resulting in a complete tumor resection. In this Perspective, we review potential applications of nanotechnologies to neurosurgery and describe how new systems, such as the one described in this issue, may be brought closer to the operating room through modifications in nanoparticle size, overcoming the obstacles presented by the blood–brain barrier, and functionalizing nanoparticle conjugates so that they reach their target at highest concentrations possible. Finally, with adaptations of the actual hand-held Raman scanner device itself, one can envision the day when “nanosurgical” procedures will be a part of the surgeon’s armamentarium.

ABSTRACTBACKGROUND AND PURPOSERequests for after‐hours emergent spine MR imaging seem to be increasing. We sought to review the trend in after hours spine MRI utilization at our institution and to determine how these results impacted therapeutic intervention.METHODSFollowing Institutional Review Board approval, reports from 179 after hours spinal MRI's performed over the past 13 years were obtained and the relevant electronic medical records were reviewed.RESULTSEmergent after hours spine MRI utilization increased from 7 per year to 23 over 13 years. Fifty‐eight percent (104/179) had significant findings. Twenty‐nine percent (52/179) of all patients imaged underwent surgery to treat pathologies identified on MR. Surgery was performed in only 2% (4/179) of these patients within 3 hours and 6% (10/179) within 6 hours of MRI completion. Five percent (8/179) had findings that were treated with radiation therapy and in 78% of these it was performed within 6–12 hours. Of those in whom steroids or antibiotics were initiated, 41% and 50% were treated within 3 hours of MR scanning, respectively.DISCUSSIONClinical use of emergent after hours spine MRI is steadily increasing at our institution. While MR imaging often discerned significant pathologies, performing these emergent studies rarely resulted in immediate surgical or radiotherapeutic intervention.

Abstract Purpose: To establish the concept of minimum clinically meaningful outcome (mCMO) of treatment in advanced solid tumors, to establish its threshold and evaluate how many superiority trials of new antineoplastic agents pass this threshold. Experimental Design: We chose overall survival as the primary indicator of patient benefit. Four conceptually different types of treatment effect can be identified in OS curves: HR, gains in median OS, proportional, and absolute increases at long-term OS. We postulated threshold levels for these four parameters defining the mCMO and set the bar at three different levels of required benefit: high, medium, and low. The postulated values were then studied by comparing our thresholds with the actual results of the pivotal superiority phase III trials on new drugs reporting on mature OS data. Results: Forty-three trials on 35,419 patients in 12 cancer types on 23 novel agents met these criteria. Only two trials reached the postulated “high” thresholds for HR and median OS. The number of “positive trials” increased to eight and 15 when the bar was lowered to the “medium” and “low” levels, respectively. The same analysis was done for proportional and absolute increases in long-term OS. No trial satisfied the criteria for long-term benefit, whereas only two and nine trials satisfied both parameters for the “medium and low” required benefit levels, respectively. Conclusions: All four OS-related parameters contribute to define the mCMO. If the bar for the mCMO is raised too much, positive trials are exceptional. Clin Cancer Res; 21(5); 1036–43. ©2014 AACR. See related commentary by Schilsky, p. 947

Comorbidity was associated with shorter overall survival but not toxicity or relapse among older women with breast cancer with good functional status.

We have previously shown that cryopreservation leads to increased apoptotic death of porcine hepatocytes intended for use in a bioartificial liver (BAL). This study was designed to determine if a broad-spectrum caspase inhibitor, IDN–1965, reduced apoptosis and increased function of cryopreserved porcine hepatocytes in static culture or in a BAL. Porcine hepatocytes were studied immediately after isolation and after 2 weeks of cryopreservation in liquid nitrogen using medium supplemented with 25 μmol/L IDN-1965 or vehicle. Both apoptotic and necrotic cells were observed in cultures of fresh and cryopreserved hepatocytes, but the percentage of apoptotic cells increased after cryopreservation. Cryopreservation in IDN-1965 improved hepatocyte viability and reduced apoptotic cell death determined by TUNEL assay. Cryopreservation of hepatocytes in IDN-1965 was also associated with reduced caspase 3-like activity, decreased release of cytochrome c from mitochondria, and a slower decline in mitochondrial membrane potential after thawing. These markers of apoptosis were lowest after cryopreservation when IDN-1965 was added to both the culture and cryopreservation medium. Functional markers of hepatocyte activity (albumin production, diazepam metabolism, urea production) were also increased after cryopreservation and culture of hepatocytes in medium supplemented with 25 μmol/L IDN-1965. Cryopreservation of porcine hepatocytes in the presence of caspase inhibitor IDN-1965 was associated with reduced apoptosis and improved function of porcine hepatocytes in both static culture and a perfused BAL. These data demonstrate that inhibition of apoptosis also preserves cell function.

Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease of synovial joints, can lead to chronic pain and structural joint damage, as well as other organ involvement, especially if not adequately controlled. Because it can affect women in their reproductive years, care of pregnant women with RA requires a delicate balance of maintaining disease control while limiting potential toxicity to the fetus and neonate. While most women experience a substantial improvement in disease activity during pregnancy, for some women their RA remains active. It can even manifest itself for the first time during pregnancy or early in the post-partum period. Optimizing disease control prior to conception is key, but utilizing disease-modifying treatments effectively and safely throughout pregnancy and lactation requires open dialogue and shared decision making. This review provides evidence-based recommendations for use of disease-modifying antirheumatic drugs (DMARDs) and biologic response modifiers to guide rheumatologists in their care of pregnant and lactating women with RA and serves as a guide to counsel male patients with RA on family planning decisions.